Cardiac Optogenetics: Enhancement by All-trans-Retinal

Area of Science:

• Optogenetics
• Cardiology
• Biophysics

Background:

• All-trans-Retinal (ATR) is a photosensitizer crucial for opsin function in optogenetics.
• Endogenous ATR levels are often assumed sufficient for mammalian optogenetic applications, but their impact on responsiveness is unclear.

Purpose of the Study:

• To investigate if exogenous ATR supplementation can enhance light responsiveness and reduce optical pacing energy in ChR2-modified cardiac cells.
• To determine the optimal dosage of ATR for improving cardiomyocyte function without toxicity.

Main Methods:

• Viral transduction of cardiac syncytium with Ad-ChR2(H134R)-eYFP.
• In vitro optical actuation (470 nm) and optical mapping to assess cellular response.
• Assessment of cardiomyocyte viability, ChR2 expression, action potential, calcium transients, and conduction.

Main Results:

• ATR supplementation (≤2 μM) improved cardiomyocyte viability and increased ChR2 membrane expression.
• 1-2 μM ATR dramatically reduced optical pacing energy by over 30-fold (to several μW/mm²).
• ATR caused action potential prolongation but did not affect conduction or significantly alter calcium transients.

Conclusions:

• Cardiomyocytes utilize non-saturating levels of ATR.
• Exogenous ATR can significantly enhance Channelrhodopsin2 performance in cardiac optogenetics.
• Carefully dosed ATR offers substantial energy savings for optogenetic cardiac stimulation.